Basic Scenario:

Basic Scenario Patient taking a pharmaceutical product expect the product to be safe and efficacious . Pharmaceutical regulatory agencies world-wide demand that the product retains its identity, quality, purity and potency for the time the product is commercially available. They also requires stability data supporting the proposed expiration date of the product.

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Various stability guidelines describing the types of studies & types of data needed. Most important guidelines are: Food and Drug Administration (FDA) International Conference on Harmonization (ICH) European Union Guidelines (EU) Japanese Guidelines (MHW) World Health Organization (WHO) Guidelines. Currently, ICH guidelines are most commonly accepted which provides information on stability testing within the areas of European union (EU), Japan and United States.

INTRODUCTION:

INTRODUCTION ICH: Is International Conference of Harmonization of technical requirements for registration of pharmaceuticals for human use. Aim : It is a unique project that brings together the regulatory authorities of Europe, Japan & U.S. and experts from the pharmaceutical industries to discuss the scientific and technical aspects of the product registration.

OBJECTIVES:

OBJECTIVES More economical use of human, animal & material resources. Elimination of un-necessary delay in global development. Availability of new medicines whilst maintaining safeguards on Quality, Safety and Efficacy and regulatory obligations to protect the public health.

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ICH : Safety The 14 Safety Guidelines that have been produced by ICH have been concerned with Carcenogenicity,Genotoxicity,Toxicity Studies etc..

ICH : Efficacy :

ICH : Efficacy The 17 Efficacy Guidelines that have been produced by ICH have been concerned with Clinical Safety, Dose Response Studies, Clinical Practices and Good Clinical Practice [E6(R1)] etc.

ICH : Multidisciplinary:

ICH : Multidisciplinary The 05 Multidisciplinary Guidelines that have been produced by ICH have been concerned with Medical Terminology, Electronic Standards for transfer of Regulatory Information[M2] and Common Technical Document [M4] etc.

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Q1A (R2) Stability Testing of New Drug Substances And Products

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1. INTRODUCTION 1.1. Objectives of the guidelines. 1.2. Scope of the guidelines. 1.3. General principles.

2. GUIDELINES:

2. GUIDELINES 2.1. DRUG SUBSTANCES 2.1.1. General 2.1.2. Stress testing : Helps in identifying the degradation products and hence the degradation pathways and the intrinsic stability of the molecule. Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effects of 1) Temperature (in 10°C increments above that for acc. Testing) 2) Humidity (75% RH or greater) 3) Hydrolysis (across wide range of pH) 4) Photo-stability testing

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2.1.3. Selection of the Batches Data from formal stability studies should be provided on at least three primary batches of the drug substance. 2.1.4. Container closure system Same as or stimulates the packaging proposed for storage and distribution. 2.1.5. Specification Is a list of tests, reference to analytical procedures, and proposed acceptance criteria, is addressed in ICH Q6A and Q6B.

2.1.6. Testing Frequency:

2.1.6. Testing Frequency Type of Study Testing Frequency Long term studies For drug substance with a proposed re-test period of at least 12 months. Every 3 months over the first year Every 6 months over the second year And annually thereafter through the proposed re test period Accelerated studies A minimum of three time points , including the initial and final time points (e.g. 0,3 and 6 months) from a 6-month study is recommended. Intermediate studies A minimum of four time points , including the initial and final time points (e.g. 0,6,9, 12 months) from a 12 month study is recommended

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2.1.8. Stability commitment 2.1.9. Evaluation 2.1.10. Statements/ Labelling A storage statement should be established for the labelling in accordance with relevant national/regional requirements. Terms such as “ambient conditions” or “room temperature” should be avoided.

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2.2. DRUG PRODUCT 2.2.1. General 2.2.2. Photo-stability testing (ICH Q1B) 2.2.3. Selection of the batches 2.2.4. Container and closure system 2.2.5. Specifications Stability studies should include testing of those attributes of the drug product that are susceptible to changes during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological & microbiological attributes, preservative content, functionality tests .

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2.2.6. Testing frequency 2.2.7. Storage conditions 2.2.7.1. General case (same as drug substance) In general, “significant change” for a drug product is defined as: A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures. Any degradation product’s exceeding its acceptance criterion Failure to meet the acceptance criteria for appearance, physical attributes and functionality tests. Failure to meet the acceptance criterion for pH Failure to meet the acceptance criteria for dissolution for 12 dosage units. A 5% water loss from semi-permeable container.

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2.2.7.2. For drug products packaged in impermeable containers: Stability studies can be conducted under any controlled or ambient humidity condition. 2.2.7.3. For drug products packaged in semi-permeable containers: Stability studies can be carried out under conditions of low relative humidity . Containers should be evaluated for potential water loss.

2.2.7. Other Comparable Approaches Developed And Reported For Non-aqueous, Solvent-based Products:

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2.2.7.2. Drug products intended for storage in a refrigerator 2.2.7.3. Drug productsintended for storage in a freezer 2.2.7.4. Drug productsintended for storage below -20°C 2.2.8. Stability commitment 2.2.9. Evaluation 2.2.10. Statements & Labeling (All above must be same as that described for drug substances)

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Q1B Photostability Testing of New Drug Substances And Drug Products

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1. GENERAL The light testing should be an integral part of the stress testing. A. Preamble: Normally, photo-stability testing is carried out on a single batch of material selected. Following studies are covered such as: Tests on the drug substance Tests on the exposed drug product outside of the immediate pack; and if necessary; Tests on the drug product in the immediate pack; and if necessary Tests on the drug product in the marketing pack.

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B. Light sources. [Defined in ISO 10977 (1993)] Appropriate control of temperature to minimize the effect of localized temperature changes should be done. Option 1: Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial day light fluorescence lamp combining visible and ultraviolet (UV) output, xenon or metal halide lamp. D65 is for outdoor daylight. ID65 is for indoor indirect daylight. Option 2: Sample should be exposed to both the cool white fluorescent and near ultraviolet lamp (from 320 to 400 nm with maximum emission energy between 350 nm and 370 nm).

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C. Procedure An overall illumination of not less than 1.2 million lux hours and an integrated near UV energy of not less than 200 watt hours/sq. mt . are focussed for direct comparisons between the drug substance and the drug product. Side-by-side exposure required with a validated chemical actinometric system to ensure that specified light exposure is obtained.

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4. ANNEX A. Quinine Chemical Actinometry Each actinometry system should be callibrated for the light source used . For that, 2% w/v aqueous solution of quinine monohydrochloride dihydrate is used. Option 1: Use 20 ml colourless ampoules . Option 2: Use 1 cm quartz cell. For both the options, prepare sample and control and measure their absorbance At and Ao respectively at 400 nm using a 1 cm path length . Measure the change in absorbance. It should be atleast 0.9 for option 1 and 0.5 for option 2.

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Q1C STABILITY TESTING OF NEW DOSAGE FORMS

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1. GENERAL This document is annex to the ICH parent stability guidelines. 2. NEW DOSAGE FORMS A new dosage form is defined as a drug product type, but contains the same active substances as included in the existing drug product approved by the pertinent regulatory authority. STABILITY STUDY PROTOCOLS Same as Q1A(R2)

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Q1D BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

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2.2. Applicability of reduced designs For the study of drug substances, Matrixing is of limited utility and bracketing is generally not applicable. 2.3. Bracketing Bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g. strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of an intermediate levels is represented by the stability of the extremes tested.

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2.3.1. Design factors 2.3.1.1. Strength Bracketing can be applied to studies with multiple strengths of identical or closely related formulations. Examples include: Capsules, tablets and oral solutions of different strengths. In cases, where different excipients are used among strengths, bracketing generally should not be applied. 2.3.2.2. Container closure sizes and/or fills. Bracketing can be applied to studies of the same container closure system where either the container size or fill varies while the other remains constant. 2.3.2. Design considerations and Potential risks.

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2.3.3. Design example :

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2.4. Matrixing Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

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2.4.1. Design factors (Same as in bracketing) 2.4.2. Design considerations A matrixing design should be balanced as far as possible so that each combination of factors is tested to the same extent over the intended duration of the study and through the last time point prior to submission.

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2.4.3. Design examples : “One-Half Reduction”

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2.4.4. Applicability and degree of reduction Knowledge of data variability. Expected stability of the product. Availability of the supporting data. Stability differences in the product within a factor or among factors. Number of factors combinations in the study. 2.4.5. Potential risk 2.5. Data Evaluation

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Q1E EVALUATION OF STABILITY DATA

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1. INTRODUCTION 1.1. Objectives of the Guideline 1.2. Background 1.3. Scope of the Guideline The parent guideline states that regression analysis is an important approach to analyzing quantitative stability data for retest period or shelf life estimation and recommends that a statistical test for batch poolability be performed using a level of significance of 0.25 .

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2. GUIDELINES 2.1. General principles This guideline is intended to provide recommendations on how to use the stability data generated in accordance with the principles detailed in ICH guideline Q1A(R2). This guideline also describes when and how extrapolation can be considered when proposing a re-test period for a drug substance or a shelf life for a drug product that extends beyond the period covered by “available data from the stability study under the long-term storage condition”. 2.2. Data presentation 2.3. Extrapolation Extrapolation is the practice of using a known data set to infer the information about a future data.

2.4. Data evaluation for re-test period or shelf life estimation for drug substances or products Intended for Room Temperature Storage:

2.4. Data evaluation for re-test period or shelf life estimation for drug substances or products Intended for Room Temperature Storage 2.4.1. No significant change at accelerated condition 2.4.1.1. Long-term and accelerated data Showing a little or no change over Time and little or no variability 2.4.1.2. Long-term or accelerated Data showing change over Time and/or variability. The drug substance or product will Remain within the acceptance criteria For that during the proposed re-test Period shelf life. Statistical analysis is of long Well term data can be useful Attribute establishing a retest Period. A statistical analysis is normally Considered un-necessary.

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2.4.2. Significant change at accelerated condition 2.4.2.1. No significant change at intermediate 2.4.2.2. Significant change at intermediate The extent of extrapolation would Depend on whether long-term data for the attribute Are amenable to statistical analysis The proposed re-test period or Shelf life should not exceed the Period covered by long-term data Data not amenable to Statistical analysis Data amenable to Statistical analysis The proposed re-test period Or shelf life can be upto 3 months beyond the period Covered by long-term data The proposed re-test period or shelf life Can be upto one-and half times, but Should not be more than 6 months Beyond, the period covered by Long-term data.

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2.6. General statistical approaches Regression analysis is considered as appropriate approach for evaluation of stability data. Upper and lower confidence limit (95%) should be calculated and compared to acceptance criterion.

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Climatic conditions in the countries where the product is to be marketed should be carefully considered during the development phase . So the world has been divided into four climatic zones based on the prevalent annual climatic conditions. Temperature and humidity determine the storage conditions and so they greatly affect the stability of the product.

2.2.2. Aqueous based drug product packaged in semi-permeable containers TYPE OF STUDY STORAGE CONDITION MINIMUM TIME PERIOD COVERED BY DATA AT SUBMISSION LONG TERM 30°C ± 2°C/35% RH ± 5% RH 12 months ACCELERATED 40°C ± 2°C/not more than 25% RH ± 5% RH 6 months The ratio of water loss rates at a given temperature is calculated By the general formula (100*ref. %RH / 100*alternative %RH)

2.2.3. Tests at elevated temperatures and/or extremes of humidity:

2.2.3. Tests at elevated temperatures and/or extremes of humidity Special transportation and climatic conditions outside the storage conditions recommended in this guideline should be supported by the additional data. Stability testing at a high humidity condition, e.g. 25°C/80%RH, is recommended for solid dosage forms in water- vapour permeable packaging viz., tablets in PVC/ aluminium blisters, intended to be marketed in territories with extremely high humidity conditions in Zone IV. 2.3. Additional considerations .